All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Bone is the second most common site of cancer metastasis, harboring over 70% of cancer metastases from prostate and breast cancers. Advanced-stage cancer patients develop bone metastases either with or without hormonal therapy, radiation therapy, chemotherapy, and immunotherapy, and currently there is no effective treatment. The pathogenesis of bone metastases remains poorly understood. Impairment of stroma cell function in the cancer microenvironment is believed to be an important step in tumor progression. Fibroblasts adjacent to cancer cells in the prostate are structurally and functionally different from normal fibroblast in the prostate. These cancer associated fibroblasts (CAFs), have different gene expression profiles from the normal fibroblasts. Cancer cells and stromal cells interact through physical contact, soluble factors and insoluble extra-cellular matrix factors. The CAFs have been shown to play a critical role in tumorigenesis. Studies show that loss of Transforming growth factor-beta type II receptor gene, in mouse fibroblast resulted in intraepithelial neoplasia in prostate. One of the mechanism by which cancer cells metastasize is by undergoing epithelial to mesenchymal transition (EMT). EMT is a conserved embryonic process where polarized immotile epithelial cells transition to apolar motile mesenchymal cells. EMT is associated with cancer migration, invasion and metastasis. The common feature of EMT is loss of E-cadherin and increase in vimentin and N-cadherin. In cancer, EMT allows benign tumors to infiltrate the surrounding tissue and metastasize to other organs.
MiRNAs are non-coding RNAs of 18-24 nucleotides that bind to sites of complementarity in the 3′ untranslated regions of messenger RNAs and inhibit their translation. A single miRNA can target several mRNA and regulate cellular pathways and cell fate. Several miRNA have been dysregulated in cancer, some of these are oncogenic (oncomiR) or they function as tumor suppressors. MiRNA have also shown to play a role in metastasis and have been termed ‘metastamirs’. Several miRNAs have been shown to promote metastasis such as miR-10b in brain cancer, miR-21 in colorectal cancer, miR-184 in PCa. A few miRNA have been described which suppress PCa bone metastasis, such as miR-143, miR-145 and miR-203.
The lack of effective treatment for cancers, and particularly drug resistant cancers, along with the prevalence of bone metastasis shows a need in the art for additional therapies as well as biomarkers to discover and develop cancer therapeutics.